Potential Therapeutic Effects of Psilocybin
Matthew W. Johnson & Roland R. Griffiths
Neurotherapeutics, 2017, 14, 734–740
Psilocybin and other 5-hydroxytryptamine2A agonist classic psychedelics have been used for centuries as sacraments within indigenous cultures. In the mid-twentieth century they were a focus within psychiatry as both probes of brain function and experimental therapeutics. By the late 1960s and early 1970s these scientific inquires fell out of favor because classic psychedelics were being used outside of medical research and in association with the emerging counter culture. However, in the twenty-first century, scientific interest in classic psychedelics has returned and grown as a result of several promising studies, validating earlier research. Here, we review therapeutic research on psilocybin, the classic psychedelic
that has been the focus of most recent research. For mood and anxiety disorders, three controlled trials have suggested that psilocybin may decrease symptoms of depression and anxiety in the context of cancer-related psychiatric distress or at least 6 months following a single acute administration. A small, open-label study in patients with treatmentresistant depression showed reductions in depression and anxiety symptoms 3 months after two acute doses. For addiction, small, open-label pilot studies have shown promising success rates for both tobacco and alcohol addiction. Safety data from these various trials, which involve careful screening, preparation, monitoring, and follow-up, indicate the absence of severe drug-related adverse reactions. Modest drug-related adverse effects at the time of medication administration are readily managed. US federal funding has yet to support therapeutic psilocybin research, although such support will be important to thoroughly investigate efficacy, safety, and therapeutic mechanisms.
Key Words : Psilocybin . psychedelic . cancer . addiction . depression . anxiety
Various indigenous societies have used classic psychedelic compounds (e.g., psilocybin,mescaline, dimethyltryptamine) for centuries, typically incorporating them into sacramental contexts [1–3]. Arthur Heffter isolated mescaline, the principal psychoactive constituent of the peyote cactus, in 1897 [4, 5], but it was only after the synthesis and identification of psychoactivity of lysergic acid diethylamide (LSD) in 1943  that these compounds received significant attention from the scientific community . There were > 1000 clinical papers published on classic psychedelics, collectively involving approximately 40,000 patients between 1950 and the mid-1960s . Aside from basic research studies, this period generated exciting preliminary evidence that classic psychedelics, when administered in the context
of psychotherapy, showed particular promise for 2 disorders: end-of-life psychiatric distress secondary to cancer [9–21] and addiction [22–29]. While some initial results were promising, most studies did not employ rigorous designs by current standards. Nonmedical classic psychedelic use, and the association between classic psychedelics and the emerging counterculture, prompted a political backlash whereby human classic psychedelic research was marginalized, government funding for classic psychedelic research ended, and regulations made such research difficult, putting an end to nearly all human classic psychedelic research. Modern research with classic psychedelics has reinitiated interest in the treatment of both cancer-related distress and addiction, with promising initial results. Although LSD was
the most studied classic psychedelic compound in the earlier era of research, recent clinical research has been primarily focused on the classic psychedelic psilocybin, which is closely pharmacologically related to LSD. Here we focus on these two potential indications for psilocybin medication development.
Over 100 species of mushrooms have been found to contain psilocybin, many falling within the genus Psilocybe . Psilocybin is a relatively small compound based on the structure of tryptamine. Psilocybin is a prodrug metabolized through in vivo dephosphorylation to psilocin, which is presumed
to be the active agent in the central nervous system . Like other classic psychedelics, the behavioral effects of psilocybin appear to be mediated primarily by agonist activity at the 5-hydroxytryptamine (HT)2A receptor; however, 5-HT2A activity does not appear to account fully for its effects . Psilocybin is characterized by low physiological toxicity  and low abuse liability, as demonstrated by marginal levels of nonhuman drug self-administration .